Long‐term mortality and cardiovascular events of seven angiotensin receptor blockers in hypertensive patients: Analysis of a national real‐world database: A retrospective cohort study

Abstract Background and Aims Although many angiotensin receptor blockers (ARBs) are widely used, comparative data regarding their impact on clinical outcomes are limited. We aimed to compare the clinical effectiveness of seven ARBs on long‐term cardiovascular outcomes in Korean patients with hypertension. Methods Using the Korean National Health Insurance Service database, the data of 780,785 patients with hypertension without cardiovascular disease (CVD) who initiated ARB treatment (candesartan, fimasartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan) in 2014 and underwent this treatment for more than 6 months, were analyzed. Cox‐regression analysis was performed using Losartan as a comparator, as it was the most widely used drug, by adjusting age, sex, diabetes, dyslipidemia, smoking, alcohol drinking, exercise, body mass index, systolic blood pressure, albuminuria, estimated glomerular filtration rate, and concomitant medications. The occurrence of mortality and the rate of major adverse cardiovascular events (MACEs) of the six ARBs was compared with that of losartan. Results The median follow‐up duration was 5.94 (interquartile range, 5.87–5.97) years. In the crude analysis of all‐cause mortality and MACEs, fimasartan exhibited the lowest event rates. In the Cox‐regression analysis with adjustment, there was no significant difference in all‐cause mortality among ARBs. The risk of MACEs with ARBs was similar to that with losartan, although the risks with irbesartan (hazard ratio [HR], 1.079; 95% confidence interval [CI], 1.033–1.127; p = 0.007) and candesartan (HR: 1.066; 95% CI, 1.028–1.106; p = 0.015) were slightly higher. Conclusion In a Korean population of patients with hypertension without CVD, six different ARBs showed similar efficacy to losartan in terms of long‐term mortality and MACEs. Further well‐designed prospective studies are required to confirm our findings.


| INTRODUCTION
Angiotensin receptor blockers (ARBs) have a protective effect on the cardiovascular system and effectively lower blood pressure (BP).
Additionally, ARBs are well-tolerated and are recommended as a firstline choice of antihypertensive medication. [1][2][3] In particular, ARBs have less common adverse effects, such as dry cough, which has a high incidence in Asian populations treated with angiotensin-converting enzyme inhibitors (ACEIs). 4 ARBs are currently the most prescribed antihypertensive drugs in many countries, including South Korea. 2,5 Currently, nine ARBs are available in the global market. While most ARBs share a common molecular structure which translates into the class effect, each ARB also has a different chemical structure associated with additional benefits. [6][7][8][9] For example, losartan, candesartan, and valsartan exhibit strong cardiovascular protective effects in patients with heart failure with reduced ejection fraction. [10][11][12] Valsartan is more beneficial in terms of long-term cardiovascular prognosis in patients with myocardial infarction. 13 Owing to their renoprotective effects, losartan and irbesartan have been suggested for the treatment of diabetic nephropathy. 14,15 In clinical practice, the prevalence of simple hypertension without complications is much higher than that of hypertension with complications. 16 Therefore, information on the use of ARBs for uncomplicated hypertension is very important. However, there is no evidence concerning which ARBs are the most suitable for patients with hypertension who do not have compelling indications, such as heart failure and myocardial infarction. As ARBs are widely prescribed antihypertensive drugs, a guide for choosing them for patients without cardiovascular disease (CVD) would be valuable to clinicians.
Recently developed ARBs, such as olmesartan and fimasartan, have strong BP-lowering effects and are widely used in clinical practice. However, evidence of their effectiveness in improving cardiovascular prognosis beyond antihypertensive effect is scarce.
Prognostic information associated with the use of these new ARBs will greatly help clinicians treat hypertension.
We conducted a retrospective analysis to compare the effects of different ARB types, including new-generation ARBs, on long-term mortality and cardiovascular events in patients with hypertension.

| Study patients
The Korean government has operated the National Health Insurance Service (NHIS) to provide medical insurance services to all Korean residents since 1989. 17 The NHIS has demographic, socioeconomic, and disability registration data to make decisions regarding eligibility and premium charging. Additionally, the NHIS has detailed data on healthcare utilization (procedures, drugs, and other treatments) submitted by medical providers for reimbursement. Using these data, the NHIS established the National Health Information Database (NHID) in 2012 to support public health policies and research. 18 We used the NHID provided by the NHIS (NHIS-NHID). This study was conducted after obtaining approval from (1) the occurrence of mortality before the date of prescription (n = 356) and (2) missing demographic characteristics and examination results (n = 547,709). Finally, we analyzed the data of 780,785 patients.

| ARBs
The ARBs investigated were candesartan, fimasartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan, according to the Anatomical Therapeutic Chemical codes maintained by World Health Organization (Supporting Information: Table S1).

| Collection of clinical variables
Demographic, clinical, and laboratory data were collected from the health check-up database in 2014. Body mass index (BMI) was calculated by dividing the weight (kg) by the square of height (m 2 ). Systolic BP (SBP) and diastolic BP were measured using an oscillometric device in the right upper arm. The measurement was performed three times at the right upper arm, and the average of lower two values were taken, the values reflecting "during drug use." Cardiovascular risk factors, including diabetes mellitus, dyslipidemia, smoking, alcohol consumption, and household income levels, were obtained using diagnostic codes and questionnaires.
After overnight fasting for approximately 12 h, the blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and creatine levels were measured. Urinalysis was performed and the presence and degree of proteinuria were assessed. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate the estimated glomerular filtration rate (eGFR). Considering impacts on cardiovascular outcomes, information on medication of other antihypertensive agents (calcium channel blockers, beta-blockers, ACEIs, and diuretics), antithrombotic agents, and statins was also obtained in cases where the medication was prescribed for more than 6 months at the time of initial ARB prescription.

| Clinical outcomes
All-cause mortality and major adverse cardiovascular events (MACEs) were the main outcome variables in this study. All-cause mortality was determined from the date of death. MACEs were defined as cardiac death, nonfatal myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization. The Korean Standard Classification of Diseases (KCD-7-based ICD-10) was used to define each MACE (Supporting Information: Table S2). The first date when the above ICD-10 codes were present in the claims data was defined as the event date.

| Statistical analysis
The χ 2 test for categorical variables and the Kruskal-Wallis test for continuous variables were performed to evaluate the differences in the distribution of demographic characteristics, incidence of MACEs, and distribution of all-cause mortality depending on the type of ARB.
Hazard ratios (HR) and 95% confidence intervals (CI) of all-cause mortality and MACEs were calculated by using a Cox proportionalhazard model adjusted for age, sex, diabetes (E10-E14), dyslipidemia (E78), smoking, alcohol drinking, exercise, household income, BMI, SBP, eGFR, and concomitant medications, including calcium antagonists, beta-blockers, ACEIs, diuretics, antithrombotic agents, and statins. The proportional assumption of the Cox analysis was conducted for Cox proportional-hazard modeling. In univariate analysis, a log-rank test was conducted. Subsequently, multiple analyses were conducted using the Cox proportional hazard model. All statistical analyses were performed using SAS 9.4 software (SAS Institute). All two-sided p < 0.05 were considered statistically significant.  The incidence of all-cause mortality and MACEs is presented in Table 2. During the median follow-up period of 5.94 (interquartile range, 5.87-5.97) years, the all-cause mortality and MACE rates of the study patients were 2.9% and 5.4%, respectively. The all-cause mortality rate was the highest in the losartan group (3.2%) and the lowest in the fimasartan group (2.3%). The incidence of MACEs was the highest in the irbesartan group (6.17%) and the lowest in the fimasartan group (4.6%). A similar trend was observed with the individual MACEs; the incidence rate was the highest in the irbesartan group (6.2%) and the lowest in the fimasartan group.

| RESULTS
The risks for all-cause mortality and MACEs according to different ARBs, compared with those of losartan, are presented in         with one class of antihypertensive drug, and ARB with two or more classes of antihypertensive drugs (Supporting Information: found that losartan was associated with a lower survival rate than that of other ARBs. 25 Antoniou et al. 26 investigated 54,186 patients with diabetes and showed that those taking telmisartan and valsartan were associated with a lower risk of development of acute myocardial infarction, heart failure, and stroke than those taking irbesartan, losartan, and candesartan. Our study differs from these two studies in that we included patients with hypertension and also showed the effectiveness of the new ARBs, fimasartan, and olmesartan. Therefore, our findings are applicable to a broader population. One observational study from Canada showed that patients with hypertension treated with irbesartan had the lowest rate of developing cardiovascular events compared with those receiving other ARBs. 27 However, the primary goal of this study was to compare the effects of ARBs with other antihypertensive drug classes, and only four ARBs (candesartan, irbesartan, losartan, and valsartan) were analyzed in this sthsrudy. Moreover, the study population taking ARBs was relatively small (n = 3490). A study in Taiwan that analyzed a large number of patients (n = 690,463) from claims data compared the effects of six ARBs (candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan) and found that olmesartan did not increase long-term cardiovascular risk T A B L E 2 Incidence of all-cause mortality and MACE compared with that by losartan. 28 This study deserves attention in that it elucidates the effect of olmesartan, unlike previous studies.
However, the study population was more heterogeneous as patients with underlying CVD were not excluded, contrary to the case in our study.
ARBs introduced in the early phase have been used in many large-